The Colorectal Cancer Gut Environment Regulates Activity of the Microbiome and Promotes the Multidrug Resistant Phenotype of ESKAPE and Other Pathogens

Matthew T. F. Lamaudière, Ramesh Arasaradnam, Gareth D. Weedall, Igor Y. Morozov

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    Abstract

    Taxonomic composition of the gut microbiota in colorectal cancer (CRC) patients is altered, a newly recognized driving force behind the disease, the activity of which has been overlooked. We conducted a pilot study on active microbial taxonomic composition in the CRC gut via metatranscriptome and 16S rRNA gene (rDNA) sequencing. We revealed sub-populations in CRC (n = 10) and control (n = 10) cohorts of over-active and dormant species, as changes in activity were often independent from abundance. Strikingly, the diseased gut significantly influenced transcription of butyrate producing bacteria, clinically relevant ESKAPE, oral, and Enterobacteriaceae pathogens. A focused analysis of antibiotic (AB) resistance genes showed that both CRC and control microbiota displayed a multidrug resistant phenotype, including ESKAPE species. However, a significant majority of AB resistance determinants of several AB families were upregulated in the CRC gut. We found that environmental gut factors regulated AB resistance gene expression in vitro of aerobic CRC microbiota, specifically acid, osmotic, and oxidative pressures in a predominantly health-dependent manner. This was consistent with metatranscriptome analysis of these cohorts, while osmotic and oxidative pressures induced differentially regulated responses. This work provides novel insights into the organization of active microbes in CRC, and reveals significant regulation of functionally related group activity, and unexpected microbiome-wide upregulation of AB resistance genes in response to environmental changes of the cancerous gut.
    Original languageEnglish
    Pages (from-to)(In-Press)
    Number of pages19
    JournalmSphere
    Volume8
    Issue number2
    Early online date27 Feb 2023
    DOIs
    Publication statusE-pub ahead of print - 27 Feb 2023

    Bibliographical note

    Copyright© 2023 Lamaudière et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited..

    Funder

    M.T.F.L. was supported by University Hospital Coventry and Warwickshire NHS Trust and Coventry University Doctoral College. We thank Rachel Constable, Patrick King, and Hugh Kikuchi for technical assistance. The authors also acknowledge the Coventry University Centre for Sport Exercise and Life Science.
    M.T.F.L., R.A. and I.Y.M. conceived and designed the study. The experimental work was carried out by M.T.F.L., G.D.W., and I.Y.M. Samples and metadata were supplied by R.A., M.T.F.L., G.D.W., and I.Y.M. analyzed the data and interpreted the results. M.T.F.L., G.D.W., and I.Y.M. wrote the manuscript. All authors were involved in editing and reviewing the manuscript.
    University Hospital Coventry and Warwickshire NHS Trust and Coventry University Doctoral College funded the project.

    Keywords

    • colorectal cancer
    • metatranscriptome
    • gut microbiota
    • multidrug resistance
    • antibiotic resistance,
    • ESKAPE pathogens

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